Composition for improving cognition and memory

ABSTRACT

The invention relates to a pharmacologically active combination, having utility in treating insomnia patients, which comprises: (a) at least one first active ingredient selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists; and (b) at least one second active ingredient selected from nicotine and nicotine receptor agonists; to use of a medicament containing component (a) with or without component (b) for alleviation of at least one adverse effect which occurs in a patient in the course of nicotine replacement therapy, or otherwise, selected from impairment of the quality of sleep, impairment of cognition and impairment of memory, as well as to a kit having utility in treating insomnia patients, which comprises components (a) and (b) in unit dosage form.

CROSS REFERENCE TO RELATED APPLICATION

This application is divisional of Ser. No. 10/555,011 filed Oct. 31,2005, which is a 35 U.S.C. 371 National Phase Entry Application fromPCT/IL2004/000330, filed Apr. 15, 2004, which claims the benefit ofIsrael Patent Application No.155666 filed on Apr. 29, 2003, thedisclosures of which are incorporated herein in their entirety byreference.

FIELD OF THE INVENTION

The present invention relates to a pharmacologically active combination,and a kit, having utility in treating insomnia patients, as well as theuse of melatonin and related compounds in the manufacture of amedicament which alleviates adverse effects which occur in the course ofnicotine replacement therapy.

BACKGROUND OF THE INVENTION

Acetylcholine is a major neurotransmitter in the brain and peripheralnervous systems; it induces a variety of physiological and behavioralresponses by binding and activating specific receptors that belong tothe muscarinic (defined on the basis of their activation by muscarine)and nicotinic (defined on the basis of their activation by nicotine)acetylcholine receptor families.

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a familyof ligand-gated ion channels that are distributed extensively throughoutthe central and peripheral nervous systems. The nAChRs are the mainmediators of fast synaptic transmission in ganglia, and therefore, arekey molecules for the processing of neural information in the autonomicnervous system. The nAChRs are involved in the control of organ systemssuch as heart, gut, and bladder. In this respect, it is important tonote that ulcerative colitis (UC) is a disease largely of non-smokers,in which nicotine is of therapeutic value. The mode of action isunknown, but may involve nicotinic acetylcholine receptors (nAChRs) inthe bowel wall (Richardson, C. E., J. M. Morgan, et al. (2003). “Effectof smoking and transdermal nicotine on colonic nicotinic acetylcholinereceptors in ulcerative colitis.” Q J Med 96: 57-65).

In the brain, beyond their role in relation to tobacco use, nAChRs areinvolved in a wide variety of behavioral functions including cognitivefunction (Araki, H., K. Suemaru, et al. (2002). “Neuronal NicotinicReceptor and Psychiatric Disorders: Functional and Behavioral Effects ofNicotine.” Jpn. J Pharmacol 88: 133-138). Both acute and chronicnicotine administration significantly improves working memoryperformance of rats in the radial-arm maze. In humans, activation ofnAChRs provides beneficial treatment for cognitive dysfunction such asAlzheimer's disease, schizophrenia, and attention deficit hyperactivitydisorder (ADHD). Nicotine has been shown to improve attentionalperformance in all of these disorders. The nAChRs participate in thepathogenesis of several brain disorders (Parkinson's and Alzheimer'sdiseases, Tourette's syndrome, schizophrenia, depression, attentiondeficit disorder). In the same diseases, clinical studies showed thatnicotine had beneficial effects, both as a therapeutic and prophylacticagent.

Activation of neuronal nicotinic acetylcholine receptors (nAChRs) hasbeen shown to maintain cognitive function following aging or thedevelopment of dementia (Picciotto, M. R. and M. Zoli (2002). “NicotinicReceptors in Aging and Dementia.” J Neurobiol 53(4): 641-55). Nicotineand nicotinic agonists have been shown to improve cognitive function inaged or impaired subjects (Rezvani, A. H. and E. D. Levin (2001).“Cognitive Effects of Nicotine.” Biol Psychiatry 49: 258-267). Smokinghas also been shown in some epidemiological studies to be protectiveagainst the development of neurodegenerative diseases. This is supportedby animal studies that have shown nicotine to be neuroprotective both invivo and in vitro. Treatment with nicotinic agonists may therefore beuseful in both slowing the progression of neurodegenerative illnesses,and improving function in patients with the disease. Nicotine addiction(primarily through tobacco smoking) is a chronic relapsing conditionthat can be difficult to treat. DSM-IV (Diagnostic and StatisticalManual of Mental Disorders—Fourth Edition, published by the AmericanPsychiatric Association, Washington D.C., 1994) has included a nicotinewithdrawal syndrome that is characterized by craving for cigarettes,irritability, anxiety, inner tension, and concentration difficulties.These symptoms are usually observed within the first two weeks aftersudden cessation of smoking although some can be experienced as early as4-6 h after the last cigarette. Nicotine replacement therapy attenuatesthese symptoms.

Nicotinic acetylcholine receptor pharmacology is becoming increasinglyimportant in the clinical symptomatology of smoking cessation andneurodegenerative diseases in general, and of cognitive and behavioralaspects in particular. Cholinesterase inhibitors (ChEls) inhibit thedegradation of acetylcholine thereby increasing its concentration in thebrain. ChEls are used for the treatment of dementia, by virtue of theirability to increase brain acetylcholine concentrations that subsequentlycause activation of nAChRs. In addition, the concept of allostericmodulation of nicotinic acetylcholine receptors has become a researchfocus for the development of therapeutic agents. Within this context,galantamine, a recently approved drug for cognition enhancement inAlzheimer's disease, modestly inhibits acetylcholinesterase and has anallosteric potentiating ligand effect at nicotinic receptors(Woodruff-Pak, D. S., C. Lander, et al. (2002). “Nicotinic CholinergicModulation: Galantamine as a Prototype.” CNS Drug Reviews 8(4):405-426).

Of major interest, however, is the fact that the activity of thedifferent subtypes of neuronal nAChR is also subject to modulation bysubstances of endogenous origin such as choline, the tryptophanmetabolite kynurenic acid, neurosteroids, and beta-amyloid peptides, andby exogenous psychotomimetic drugs such as phencyclidine and ketamine(Pereira, E. F., C. Hilmas, et al. (2002). “Unconventional Ligands andModulators of Nicotinic Receptors.” J Neurobiol 53(4): 479-500).Recently, sustained-release bupropion (bupropion SR) treatment was foundefficacious in smoking cessation (Jorenby, D. (2002). “Clinical Efficacyof Bupropion in the Management of Smoking Cessation.” Drugs 62(2):25-35).

While nicotinic cholinergic receptors are present in many brain regions,it remains unclear which are important for the effects of nicotine onsleep and daytime alertness, although it is clear that such effects arepresent. There is also little literature on the effects of nicotine onsleep in non-smokers, while early nicotine withdrawal has beenassociated with sleep fragmentation in smokers (Wetter, D. W., M. C.Diore, et al. (1995). “Tobacco Withdrawal and Nicotine ReplacementInfluence Objective Measures of Sleep.” Journal of Consulting andClinical Psychology 63(4): 658-667).

One of the significant observed side effects of patch nicotinereplacement is insomnia (Jorenby, D. E., S. J. Leischow, et al. (1999).“A Controlled Trial of Sustained-Release Bupropion, A Nicotine Patch, orBoth for Smoking Cessation.” The New England Journal of Medicine 340(9):685-691). Based on the known stimulating effects of nicotine on cortisolsecretion, markedly reduced cortisol concentrations are likely to be aneuroendocrine consequence of abstinence from smoking. Nicotinereplacement therapy may activate the HPA axis and increase cortisollevels. Such activation may presumably lead to sleep problems as recentfindings suggest that high cortisol levels are associated with poorsleep quality (Rodenbeck, A., G. Huether, et al. (2002). “Interactionsbetween evening and nocturnal cortisol secretion and sleep parameters inpatients with severe chronic primary insomnia.” Neuroscience Letters324: 159-163; and Vgontzas, A. N., E. O. Bixler, et al. (2001). “ChronicInsomnia Is Associated with Nyctohemeral Activation of theHypothalamic-Pituitary-Adrenal Axis: Clinical Implications.” J ClinEndocrinol Metab 86(8): 3787-3794).

Melatonin, the hormone secreted at night by the pineal gland, has sleeppromoting properties when given at daytime, namely when its levels inthe body are low. The effect observed, shortening of sleep latency, isregarded as evidence of hypnotic activity of a drug (benzodiazepines andnon-benzodiazepines), though hypnotic drugs usually impair daytimevigilance. Indeed, melatonin, like hypnotic drugs, produces asignificant decrease in vigilance and performance during the first hoursafter its administration (Wurtman U.S. Pat. No. 5,641,801 Jun. 24, 1997;Graw, P., E. Werth, et al. (2001). “Early morning melatoninadministration impairs psychomotor vigilance.” Behavioural BrainResearch 121: 167-172; Dollins, A. B., H. J. Lynch, et al. (1993).“Effect of pharmacological daytime doses of melatonin on human mood andperformance.” Psychopharmacology 112: 490-496).

Moreover, an expert in the field may report that melatonin in fact harmsvigilance, as indeed has been found in depressed patients following oneweek of daily administration of oral melatonin (Sherer, M. A., H.Weingartner, et al. (1985). “Effects of melatonin on performance testingin patients with seasonal affective disorder.” Neuroscience Letters 58:277-82). Therefore, at low doses (0.3-10 mg), melatonin'spharmacological activity is regarded as hypnotic. As such, it is notexpected to improve psychomotor or cognitive performance shortly afterits administration, or improve daytime functioning.

The sleep inducing effects of melatonin at night have been demonstratedin elderly patients with insomnia, in whom melatonin production is lowdue to aging and diseases, and additional cases in which melatonindeficiency was apparently involved. Administration of melatonin at night(0.3-2 mg daily for 1-3 weeks) improves sleep compared to placebo inelderly subjects with insomnia (Haimov, I., P. Lavie, et al. (1995).“Melatonin replacement therapy of elderly insomniacs.” Sleep 18(7):598-603; 18:598-603; Garfinkel, D., M. Laudon, et al. (1995).“Improvement of sleep quality in elderly people by controlled-releasemelatonin.” The Lancet 346: 541-544). However, melatonin may be lesseffective at night in younger patients with insomnia who apparentlyproduce sufficient amounts of melatonin endogenously (James, S. P., D.A. Sack, et al. (1990). “Melatonin administration in insomnia.”Neuropsychopharmacology 3: 19-23; James, S. P., W. B. Mendelson, et al.(1987). “The effect of melatonin on normal sleep.”Neuropsychopharmacology 1: 41-44). In a recent study melatonin (0.5 mg)was administered as immediate-release (evening or mid-nightadministration) or prolonged-release forms (evening administration) to agroup of patients with age-related sleep maintenance insomnia. All threemelatonin treatments shortened latencies to persistent sleep but werenot effective in sustaining sleep (Hughes, R. J., R. Sack, et al.(1998). “The role of melatonin and circadian phase in age-relatedsleep-maintenance insomnia: assessment in a clinical trial of melatoninreplacement.” Sleep 21(1): 52-68). Therefore, melatonin may not beeffective in promoting sleep at night in patients who produce sufficientamounts of the hormone endogenously.

Studies in vivo have failed to demonstrate significant effects ofnicotine on the endogenous melatonin production in animals and humans(Tarquini, B., F. Perfetto, et al. (1994). “Daytime circulatingmelatonin levels in smokers.” Tumori 80: 229-232; Gaddnas, H., K.Pietila, et al. (2002). “Pineal melatonin and brain transmittermonoamines in CBA mice during chronic oral nicotine administration.”Brain Research 957: 76-83). Thus, it could not have been inferred thatmelatonin might alleviate sleep problems associated with nicotinetreatment, either in the form of cigarette smoking or upon nicotinereplacement therapy for smoking cessation. In one study, administrationof exogenous melatonin alone without nicotine replacement therapy,shortly after smoking cessation (4 hours), alleviated symptoms of acutenicotine withdrawal, compared to placebo treated control subjects;administration of melatonin (4 mg, i.p.) was not associated with anincrease of a feeling of sedation or fatigue in these subjects(Zhdanova, I. and V. Piotrovskaya (2000). “Melatonin treatmentattenuates symptoms of acute nicotine withdrawal in humans.”Pharmacology, Biochemistry and Behavior 67: 131-135). These data suggestthat melatonin alone may alleviate symptoms of smoking cessation, butwould not suggest that at the same time it would also be able toalleviate symptoms of nicotine replacement therapy. Since on the onehand, nicotine does not suppress melatonin production, and on the otherhand melatonin may not be effective in improving sleep in subjects whoproduce sufficient amounts of the hormone, and, in addition, anyhypnotic activity of melatonin is expected to be associated with adeterioration in cognition and performance, nothing in the availabledata suggest that melatonin might be a useful agent in alleviating theinsomnia incurred by nicotine replacement therapy or that it wouldenhance the cognitive effects of nicotine.

In Markus, R. P., J. M. Santos, et al. (2003). “Melatonin NocturnalSurge Modulates Nicotinic Receptors and Nicotine-Induced [3H]-GlutamateRelease in Rat Cerebellum Slices.” JPET Fast Forward. 45625, it isreported that the [(3)H]-glutamate overflow induced by alpha7 nAChRsactivation was higher during the dark phase (when melatonin is producedendogenously) and that the nocturnal increase in nicotine-evoked[(3)H]-glutamate release is imposed by a nocturnal surge of melatonin,as it is abolished when pineal melatonin production is inhibited byeither maintaining the animals in constant light for 48 hours or byinjecting propranolol just before lights off for two days; it isconcluded that nicotine-evoked [(3)H]-glutamate release in ratcerebellum presents a diurnal variation, driven by the endogenousnocturnal pineal melatonin surge.

Markus, R. P. M., A, W. M. Zago, et al. (1996). “Melatonin modulation ofpresynaptic nicotinic acetylcholine receptors in the rat vas deferens.”The Journal of Pharmacology and Experimental Therapeutics 279: 18-22,reported higher sensitivity to nicotine in prostatic portions incubatedwith exogenous melatonin, and in organs from animals killed at night,after the rise of endogenous melatonin, and concluded that this isprobably due to the appearance of low-affinity neuronal nicotinic AChbinding sites.

The Markus articles appear to imply that melatonin enhances the effectsof nicotine. If extrapolated to humans, the Markus results could explainthe beneficial effects of melatonin during smoking cessation, in absenceof exogenous nicotine administration, as demonstrated by Zhdanova.However, they would also imply that melatonin would exacerbate thenicotine-induced insomnia in smoking cessation, in subjects treated withnicotine.

Oral delivery of nicotine for therapeutic purposes has been proposed,e.g. in U.S. Pat. No. 6,183,775 (see below), as well as in WO8803803,WO02076211 and published US Patent Application 2001029959.

Published US Patent Applications 20030051728 and 20030062042 disclosemethods of delivering a physiologically active compound (e.g. nicotineand melatonin among many others) as an aerosol.

U.S. Pat. No. 6,183,775 discloses a controlled release lozengecomprising active substances, among which are mentioned nicotine andmelatonin.

U.S. Pat. No. 6,068,853 describes a transdermal delivery device fordelivery of active agents, and mentions types, as well as specificinstances, of active agents, e.g. melatonin and nicotine.

U.S. Pat. No. 5,284,660 describes a device which delivers drugs to theskin or to the mucosa at predetermined intervals. The deliverable drugsmay be e.g., nicotine (for daytime administration) or melatonin (fornight-time administration). Neither this patent, nor any other of thepatent documents (patents and published patent applications) mentionedherein, describe or suggest combined administration of nicotine andmelatonin.

The entire contents of the patent documents (patents and publishedpatent applications) mentioned herein are incorporated by reference inthe present patent application.

It has now surprisingly been found, in relation to nicotine treatment,that exogenous melatonin produces a significantly greater benefit ininsomnia patients who are habitual smokers compared to non-smokers. Thesynergistic effect of nicotine and melatonin on sleep has not beenobserved before, and is of potential utility in clinical interventionsthat involve nAChRs activation or particularly nicotine administration,to alleviate sleep problems incurred by these treatments. Besides,concomitant treatment by melatonin and nicotinic acetylcholine receptormodulation offers potentially significant benefits over nicotinicactivation alone, in improving cognitive function in the elderly ingeneral and in Alzheimer's disease patients in particular. Since sleepis important for memory consolidation (Maquet, P. (2001). “The Role ofSleep in Learning and Memory.” Science 294: 1048-1052), concomitantmelatonin-nicotinic therapy might also be expected to improve next daycognitive and memory functions due to enhanced sleep-dependent memoryconsolidation.

SUMMARY OF THE INVENTION

In general terms, the invention concerns the administration of melatoninand related compounds, either in regular or prolonged release dosageform (or any other form of administration) in order to treat nAChRsactivation related insomnia (in smoking cessation as well as othermedical indications), and for improvement of cognitive function andmemory.

Thus, the present invention provides in one aspect, a pharmacologicallyactive combination, having utility in treating insomnia patients, whichcomprises: (a) at least one first active ingredient selected frommelatonin, other melatonergic agents, melatonin agonists and melatoninantagonists; and (b) at least one second active ingredient selected fromnicotine and nicotine receptor agonists. In the pharmacologically activecombination of the invention, components (a) and (b) may be formulatedseparately, or may be formulated together in a single formulation.

In another aspect, the invention consists of use of at least one firstactive ingredient (a) selected from melatonin, other melatonergicagents, melatonin agonists and melatonin antagonists, in the manufactureof a first medicament which alleviates at least one of the followingadverse effects which occur in the patient in the course of nicotinereplacement therapy, namely, impairment of the quality of sleep,impairment of cognition and impairment of memory, wherein said patientmay optionally be receiving simultaneously a second medicamentcomprising at least one second active ingredient (b) selected fromnicotine and nicotine receptor agonists.

In yet another aspect, the invention consists of use of at least onefirst active ingredient (a) selected from melatonin, other melatonergicagents, melatonin agonists and melatonin antagonists, in the manufactureof a first medicament which in the presence of a second medicament asdefined below alleviates, in patients other than those receivingnicotine replacement therapy, at least one of the following adverseeffects, namely, impairment of the quality of sleep, impairment ofcognition and impairment of memory, wherein said second medicamentcomprises at least one second active ingredient (b) selected fromnicotine and nicotine receptor agonists.

In still another aspect, the present invention provides a kit havingutility in treating insomnia patients, which comprises:

(A) a first pharmaceutical formulation in unit dosage form comprising,in addition to at least one diluent, carrier or adjuvant, at least onefirst active ingredient selected from melatonin, other melatonergicagents, melatonin agonists and melatonin antagonists; and

(B) a second pharmaceutical formulation in unit dosage form comprising,in addition to at least one diluent, carrier or adjuvant, at least onesecond active ingredient selected from nicotine and nicotine receptoragonists;

wherein the dosage units in (A) and (B) are independently selected fromthose adapted for oral, rectal, parenteral, transbuccal, intrapulmonaryor transdermal administration.

DETAILED DESCRIPTION OF THE INVENTION

The pharmacologically active combination according to the invention, aswell as each medicament in the uses of the invention, may becharacterized by at least one of the following features:

-   -   (i) it comprises also at least one diluent, carrier or adjuvant;    -   (ii) it is in the form of dosage units, and the dosage units are        adapted for oral, rectal, parenteral, transbuccal,        intrapulmonary or transdermal administration;    -   (iii) it is a controlled, sustained or prolonged release        formulation;    -   (iv) it is in a depot form which will release the active        ingredients slowly in the body, over a preselected time period;    -   (v) ingredient (a) is melatonin;    -   (vi) ingredient (b) is nicotine;    -   (vii) it comprises at least one melatonin receptor modifier        and/or melatonin profile modifier;    -   (viii) the first and second active ingredients (a) and (b) are        formulated in a single formulation.

The pharmacologically active combination according to the invention, aswell as each medicament in the uses of the invention, may be in the formof dosage units, wherein each dosage unit contains at least one of theactive ingredients in an amount which lies within the range of0.025-100, preferably 0.25 to 50 and more preferably 0.5 to 40 mg.

The kit provided by the present invention is preferably furthercharacterized by at least one of the following features:

-   -   i) at least one of (A) and (B) is a controlled, sustained or        prolonged release formulation;    -   ii) at least one of (A) and (B) is in a depot form which will        release the said active ingredients slowly in the body, over a        preselected time period;    -   iii) said at least one first active ingredient comprises        melatonin;    -   iv) said at least one second active ingredient comprises        nicotine;    -   v) (A) comprises also at least one melatonin receptor modifier        and/or melatonin profile modifier;    -   vi) (A) comprises also at least one further active ingredient        selected from nicotine and nicotine receptor agonists;    -   vii) said first and second active ingredients, and said further        active ingredient if present, are present in said dosage units        in an amount which lies within the range of 0.025-100 mg,        preferably 0.25 to 50 mg, more preferably 0.5 to 40 mg.

Without prejudice to the generality of this aspect of the invention, itis presently preferred that (A) and (B) are each in the form of atransdermal patch. Such a kit is exemplified, by way of illustrationonly, by a kit comprising the daytime and nighttime patches described inFormulation Example (C), below.

In another presently preferred embodiment of the kit of the presentinvention, (A) may be in the form of a controlled release tablet fororal administration and (B) in the form of a transdermal patch. Such akit is exemplified, by way of illustration only, by a kit comprising themelatonin-containing tablets and the nicotine-containing patch describedin Formulation Examples (A) and (B), below.

In accordance with the present invention, it was unexpectedly found thatwhile melatonin levels in smokers and non smokers were comparable,administration of melatonin (controlled release 2 mg) daily in theevening for 4 weeks had a significantly greater effect on theimprovement of sleep quality in smoking than non-smoking patients withinsomnia aged 55 years and older over the values found with placebotreatment of the same individuals (e.g. as shown in Example 1).

In addition, administration of melatonin (controlled release 2 mg) dailyin the evening for 3 weeks had a significantly greater effect in smokingthan non-smoking patients with insomnia aged 20-55 years in theimprovement of sleep quality (e.g. as shown in Example 2).

Moreover, administration of melatonin (controlled release 2 mg) daily inthe evening for 3 weeks had a significantly greater effect in smokingthan non-smoking patients with insomnia aged 55 years and over withrespect to the enhancement of psychomotor skills (e.g. as shown inExample 3).

Even more surprising was the finding that a single administration ofmelatonin (controlled release 2 mg) resulted in a significantly improvedmemory recall over that under placebo treatment in the same subjects whowere smokers or ceased smoking less then 6 months before the trial,compared to that in non-smokers (e.g. as shown in Example 4).

The invention will now be illustrated by the following non-limitingexamples.

EXAMPLE 1

The effect of a controlled release formulation of melatonin onsubjectively assessed sleep quality in 17 elderly insomnia patients(aged 66.9 (SD 5.4) years) were studied in a randomized, double-blind,crossover study. Basal excretion of the main melatonin metabolite6-sulfatoxymentonin in urine over the nocturnal period (8 p.m.-8 a.m.)was measured and the subjects were treated for 1 week with placebo toestablish baseline characteristics followed by a two-period crossoverdesign (4 weeks on either melatonin controlled release 2 mg or placebo)separated by a washout period (1 week). On the last week of the baselineand treatment periods patients were asked to assess the quality of theirsleep the previous night by ticking a 140 mm visual analog scale. Thedistance (in mm) of the patient mark from the left hand side of thescale was measured and a higher number indicated better sleep. Thedifference from placebo values in the patient evaluation of restfulsleep was calculated for smoking and non-smoking patients. There were nosignificant differences in the amount of nocturnal 6-sulfatoxymentoninexcreted by smokers and non-smokers in the study population (3.5+1.5 vs.6.3+5 μg 6-sulfatoxymentonin, respectively). Surprisingly, it was foundthat the improvement in quality of sleep with melatonin over that withplacebo was significantly greater in smokers showing a synergisticeffect of the melatonin and nicotine (Table 1). No difference was foundin the response to placebo between the smokers and non-smokers.

TABLE 1 Effects of melatonin over placebo on subjectively assessedquality of sleep in smoker and non-smoker insomnia patients. Non smokersSmokers Significance Parameter (n = 4) (n = 10) (t-test) Mean change (inmm) in −2.8 15 P = 0.003 perceived quality of sleep with melatonin overplacebo Mean nocturnal 3.5 6.3 P = 0.29  6-sulfatoxymenlatonin excretion(μg/night)

EXAMPLE 2

The effect of a controlled release formulation of melatonin onsubjectively assessed sleep quality were studied in a mixed age insomniapatients population (aged 20-80 years). The subjects were treated for 1week with placebo to establish baseline characteristics and then for 3weeks with 1 mg per night of controlled release melatonin or placebo. Onthe last three days of the baseline and treatment periods patients wereasked to assess the quality of their sleep the previous night using theLeeds Sleep Evaluation Questionnaire (Parrott, A. C. and I. Hindmarch(1980). “The Leeds sleep evaluation questionnaire inpsychopharmacological investigations—a review.” Psychopharmacology(Berl) 71(2): 173-9) which comprises two 100 mm visual analog scalesrelating to sleep quality. The distance of the patient mark from theright handside in mm was measured and the mean answer of the twoquestions was averaged across the 3 consecutive nights. A responder wasdefined as a patient showing improvement of 10 mm or more on theaveraged value. Surprisingly it was found that regardless of age therewas a significantly higher rate of responders among the smokers (62%,n=16) than among the non-smokers (40%, n=43, p=0.002). There was nodifference in responder rate to placebo between the smokers (46%, n=13)and non-smokers groups (44% n=53, p=0.89, chi-square test).

EXAMPLE 3

The effect of a controlled release formulation of melatonin onpsychomotor performance (total reaction time, TRT, and Mean reactiontime, MRT) in 40 elderly insomnia patients (aged 60.8 (SD 0.8) years)were studied. The subjects were treated for 2 weeks with placebo(baseline) and 3 weeks with 2 mg per night of controlled releasemelatonin. On the last two days of treatment psychomotor tests weretaken by all patients to assess daytime vigilance. The improvement inPsychomotor skills in patients treated with melatonin were significantlyhigher in the smokers (−38.95 msec on TRT and −36.07 on MRT) compared tonon-smokers group (−5.21 and 0.62 msec, p=0.05 and p=0.03,respectively).

EXAMPLE 4

The effect of melatonin (2 mg controlled release formulation) andplacebo on memory recall (Rivermead story test) were assessed in 16elderly volunteers (>55 years; aged 59 (SD 3.2) years). In a randomised,double-blind, crossover study the subjects were given a tablet ofplacebo in the evening to establish baseline and then a tablet ofmelatonin or placebo in a random order in the evening with one week withno treatment in between treatments. The Rivermead test was given to thepatients at 2 and 12.5 hours after the administration of the tablet.Surprisingly, melatonin resulted in improvement of memory tasks in thefirst hours of its administration over the respective placebo values inthe same subjects. Memory efficiency is increased with controlledrelease 2 mg melatonin for both recalls (immediate and delayed) in thesubjects who were smoking or ceased smoking within the last 6 monthsprior to the study than non-smokers compared to baseline or crossoverplacebo.

TABLE 2 Mean number of recalled elements of the story and Differencefrom placebo of memory performance at 2 hours after intake of melatoninor placebo. Smokers Non-smokers Significance Time after dosing (n = 4)(n = 12) (t-test) Number recalls - Melatonin 14.8 9.8 P = 0.056 Numberrecalls - placebo 12.2 12.1 P = 0.33  Difference in recalls under 3.5−2.41 P = 0.043 melatonin and placebo

Examples of non-limiting pharmaceutical formulations, which may beutilized in accordance with the present invention, are given below.

FORMULATION EXAMPLES (A) Controlled-Release Melatonin

Controlled-release formulations for oral administration were prepared bycompressing in a 7 mm cylindrical punch, at 2.5 tons, after dry mixingof the powdered materials, namely, 2 mg melatonin (Lipomed Co.,Switzerland) and acrylic resin carrier (Rohm Pharma), so that theproduct contained EUDRAGIT® RSPO 35.3%, lactose 16.7%. calcium hydrogenphosphate 41.4%, talc 1.3%, magnesium stearate 4%, melatonin 1.3%. Itmay be tabletted to contain e.g. 1 mg or 2 mg melatonin.

(B) Formulation Containing Nicotine Only

In the present example a transdermal patch is made that can hold anddeliver sufficient nicotine to be effective for a period of 24 hours.The patch is typically replaced once a day, and can be used for smokingcessation therapy or in other situations where systemic nicotinedelivery is indicated. A melatonin tablet given at night is used toalleviate the insomnia caused by the nicotine therapy. Melatonin isprovided during the night, preferably as a controlled release tabletsuch as that described in Formulation Example (A), above, that can holdand deliver sufficient melatonin to be effective for e.g. the nocturnal8 hour period.

For preparation of 1 g of the patch adhesive matrix, acetone (0.21 g)isopropyl alcohol (0.023 g) and ethyl alcohol (0.117 g) were placed in astirring tank and EUDRAGIT® E100 (0.422 g) was added in portions withstirring until completely dissolved. Dibutyl sebacate (0.19 g) was thenadded and stirring continued for 20 minutes, followed by succinic acid(0.038 g) with stirring, which was continued for 10 minutes. A solutionof nicotine-loaded adhesive was made by adding 33 wt % liquid nicotineto the adhesive matrix solution, and stirring for 30 minutes. A layer ofbacking material grade 3M-1005 (100 cm²) was spread in a tray andcovered with the matrix mixture. The mixture was cast with a bladeheight set at 1500 m_(C). The dish was covered, and the matrix was leftfor the solvent to evaporate at room temperature. Patches with an areaof 10 cm² were cut from the finished matrix. An inert release 3M-1512liner was applied to the adhesive surface and removed immediately priorto application of the device to the skin. The amount of nicotine perpatch was 33 mg to be delivered over the 24 hour period.

(C) Formulation Containing Both Nicotine and Melatonin

It is contemplated that the formulation of this Example will be used fornighttime delivery of sufficient amounts of nicotine and melatonin to beeffective for a period of 8-12 hours (after which it is replaced), andthat it would preferably be used in conjunction with a separate patchfor daytime delivery of nicotine only over a period of 12-16 hours, forsmoking cessation therapy or in other situations where systemic nicotinedelivery is indicated without causing insomnia. The daytime patch istypically replaced after 12-16 hours, and may be prepared as describedin example (B), above, except that the strength of the nicotine solutionis 21 wt % instead of 33 wt %.

For preparation of 1 g of the night-time patch adhesive matrix, acetone(0.21 g) isopropyl alcohol (0.023 g) and ethyl alcohol (0.117 g) wereplaced in a stirring tank and EUDRAGIT® E100 (0.422 g) was added inportions with stirring until completely dissolved. Dibutyl sebacate(0.19 g) was then added and stirring continued for 20 minutes, followedby succinic acid (0.038 g) with stirring, which was continued for 10minutes. A solution of nicotine- and melatonin-loaded adhesive was madeby suspending 23 wt % melatonin in 0.35 g of acetone/isopropylalcohol/ethyl alcohol mixture (9:1:5) and adding 12 wt % liquidnicotine, adding the suspension to the adhesive matrix solution, andstirring for 30 minutes. A layer of backing material grade 3M-1005 (100cm²) was spread in a tray and covered with the matrix mixture. Themixture was cast with a blade height set at 2500 m_(C). The dish wascovered, and the matrix was left for the solvent to evaporate at roomtemperature. Patches with an area of 10 cm² were cut from the finishedmatrix. An inert release 3M-1512 liner was applied to the adhesivesurface and removed immediately prior to application of the device tothe skin. Each patch contained 12 mg of nicotine and 23 mg of melatoninto be delivered over the 8-12 hour nocturnal period.

While particular embodiments of the invention have been particularlydescribed hereinabove, it will be appreciated that the present inventionis not limited thereto, since as will be readily apparent to skilledpersons, many modifications or variations can be made. Suchmodifications or variations which have not been detailed herein aredeemed to be obvious equivalents of the present invention.

1. A pharmacologically active combination comprising: (a) a first activeingredient selected from melatonin or a melatonin agonist; and (b) atleast one second active ingredient selected from nicotine or a nicotinereceptor agonist; wherein said first active ingredient is provided incontrolled, sustained or prolonged release form and saidpharmacologically active combination contains said first and secondactive ingredients in an amount effective for treatment of cognitivedysfunction and sleep impairment.
 2. The pharmacologically activecombination of claim 1, which is characterized by at least one of thefollowing features: (i) each ingredient comprises also at least onediluent, carrier or adjuvant; (ii) the pharmacologically activecombination is in the form of at least one dosage unit, and said atleast one dosage unit for at least said first active ingredient isadapted for oral, rectal, parenteral, transbuccal, intrapulmonary ortransdermal administration; (iii) the pharmacologically activecombination is in a depot form which will release said at least one ofsaid first and second active ingredients slowly in the body, over apreselected time period; (iv) said ingredient (a) is melatonin; (v) saidingredient (b) is a nicotine receptor agonist; (vi) said first andsecond active ingredients (a) and (b) are formulated in a singleformulation.
 3. The pharmacologically active combination of claim 2,which is in said form of dosage units, wherein each dosage unit containsat least one of said active ingredients in an amount which lies withinthe range of 0.025-100 mg.
 4. The pharmacologically active combinationof claim 3, wherein said amount lies within the range of 0.25 to 50 mg.5. The pharmacologically active combination of claim 4, wherein saidamount lies within the range of 0.5 to 40 mg.
 6. A method of treating apatient suffering from cognitive dysfunction and sleep impairmentcomprising administering to said patient a first medicament and a secondmedicament, said first medicament comprising at least one first activeingredient (a) selected from melatonin or a melatonin agonist, and saidsecond medicament comprising at least one second active ingredient (b)selected from nicotine or a nicotine receptor agonist.
 7. The method ofclaim 6, wherein each of said medicaments is characterized respectivelyby at least one of the following features: (i) at least one of saidmedicaments further comprises at least one diluent, carrier or adjuvant;(ii) at least one of said medicaments is in the form of dosage units,and said dosage units are adapted for oral, rectal, parenteral,transbuccal, intrapulmonary or transdermal administration; (iii) atleast one of said medicaments is a controlled sustained or prolongedrelease formulation; (iv) at least one of said medicaments is in a depotform which will release at least one of said active ingredients slowlyin the body, over a preselected time period; (v) said ingredient (a) ismelatonin; (vi) said ingredient (b) is a nicotine receptor agonist;(vii) said first and second active ingredients (a) and (b) areformulated in a single formulation.
 8. The method according to claim 7,wherein each of said first and second medicaments is in the form ofdosage units, wherein each said dosage unit contains at least one ofsaid active ingredients in an amount which lies within the range of0.025-100 mg.
 9. The method of claim 8, wherein said amount lies withinthe range of 0.25-50 mg.
 10. The method of claim 9, wherein said amountlies within the range of 0.5-40 mg.
 11. The method of claim 6, whereinsaid patient suffers from sleep impairment and at least one ofAlzheimer's disease, schizophrenia, and attention deficit hyperactivitydisorder (ADHD).
 12. The method of claim 6, wherein said patient suffersfrom sleep impairment and Alzheimer's disease.
 13. The method of claim6, wherein said nicotine receptor agonist is an acetylcholinesteraseinhibitor.
 14. The method of claim 6, wherein said patient furthersuffers from insomnia.
 15. A kit having utility in treating a patientsuffering from cognitive dysfunction and sleep impairment comprising:(a) a first pharmaceutical formulation in unit dosage form comprising,in addition to at least one diluent, carrier or adjuvant, at least onefirst active ingredient selected from melatonin or a melatonin agonist,which is in a form adapted for controlled, sustained or prolongedrelease; and (b) a second pharmaceutical formulation in unit dosage formcomprising, in addition to at least one diluent, carrier or adjuvant, atleast one second active ingredient selected from nicotine or a nicotinereceptor agonist; wherein the dosage units in (a) and (b) areindependently selected from those adapted for oral, rectal, parenteral,transbuccal, intrapulmonary or transdermal administration.
 16. The kitof claim 15, wherein said component (b) is not in a controlled,sustained or prolonged release form.
 17. The kit of claim 15, which isfurther characterized by at least one of the following features: (i)said at least one first active ingredient comprises melatonin; (ii) saidat least one second active ingredient comprises a nicotine receptoragonist; (iii) said first and second active ingredients, and saidfurther active ingredient if present, are present in said dosage unitsin an amount which lies within the range of 0.025-100 mg.
 17. The kit ofclaim 16, wherein said first and second active ingredients, and saidfurther active ingredient if present, are present in said dosage unitsin an amount which lies within the range of 0.25 to 50 mg.
 18. The kitof claim 17, wherein said first and second active ingredients, and saidfurther active ingredient if present, are present in said dosage unitsin an amount which lies within the range of 0.5 to 40 mg.